自闭症谱系障碍中皮质厚度的个体差异及其基因组基础

Interindividual Differences in Cortical Thickness and Their Genomic Underpinnings in Autism Spectrum Disorder.

作者信息

Ecker Christine, Pretzsch Charlotte M, Bletsch Anke, Mann Caroline, Schaefer Tim, Ambrosino Sara, Tillmann Julian, Yousaf Afsheen, Chiocchetti Andreas, Lombardo Michael V, Warrier Varun, Bast Nico, Moessnang Carolin, Baumeister Sarah, Dell'Acqua Flavio, Floris Dorothea L, Zabihi Mariam, Marquand Andre, Cliquet Freddy, Leblond Claire, Moreau Clara, Puts Nick, Banaschewski Tobias, Jones Emily J H, Mason Luke, Bölte Sven, Meyer-Lindenberg Andreas, Persico Antonio M, Durston Sarah, Baron-Cohen Simon, Spooren Will, Loth Eva, Freitag Christine M, Charman Tony, Dumas Guillaume, Bourgeron Thomas, Beckmann Christian F, Buitelaar Jan K, Murphy Declan G M

机构信息

Department of Child and Adolescent Psychiatry, University Hospital, Goethe University, Frankfurt am Main, Germany (Ecker, Bletsch, Mann, Schaefer, Yousaf, Chiocchetti, Bast, Freitag); Department of Forensic and Neurodevelopmental Sciences (Ecker, Pretzsch, Dell'Acqua, Puts, Loth, Murphy) and Department of Psychology (Tillmann, Charman), Institute of Psychiatry, Psychology, and Neuroscience, King's College London; Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands (Ambrosino, Durston); Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems, University of Trento, Istituto Italiano di Tecnologia, Rovereto, Italy (Lombardo); Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, U.K. (Lombardo, Warrier, Baron-Cohen); Department of Psychiatry and Psychotherapy (Moessnang, Baumeister, Meyer-Lindenberg) and Department of Child and Adolescent Psychiatry (Moessnang, Baumeister, Banaschewski), Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands (Floris, Zabihi, Marquand, Beckmann, Buitelaar); Human Genetics and Cognitive Functions Unit, Institut Pasteur, University of Paris, Paris (Cliquet, Leblond, Moreau, Dumas, Bourgeron); Centre for Brain and Cognitive Development, Birkbeck, University of London, London (Jones, Mason); Center for Neurodevelopmental Disorders (KIND), Center for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet and Stockholm Health Care Services, and Department of Child and Adolescent Psychiatry, Stockholm Health Care Services, Region Stockholm, Sweden (Bölte); Department of Child and Adolescent Neuropsychiatry, Gaetano Martino University Hospital, University of Messina, Messina, Italy (Persico); Roche Pharmaceutical Research and Early Development, NORD Discovery and Translational Area, Roche Innovation Center Basel, Switzerland (Spooren).

出版信息

Am J Psychiatry. 2022 Mar;179(3):242-254. doi: 10.1176/appi.ajp.2021.20050630. Epub 2021 Sep 10.

DOI:10.1176/appi.ajp.2021.20050630

PMID:34503340

Abstract

OBJECTIVE

Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions.

METHODS

The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features.

RESULTS

In addition to significant between-group differences in "core" ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals' total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission.

CONCLUSIONS

The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.

摘要

目的

自闭症谱系障碍（ASD）伴有高度个体化的神经解剖学偏差，这些偏差可能与不同的基因型和临床表型相关。本研究旨在将脑解剖结构的差异与特定的生物学途径联系起来，为靶向治疗干预铺平道路。

方法

作者在欧盟自闭症干预纵向欧洲项目（LEAP）中，对360名患有ASD的个体和279名发育正常的对照受试者（年龄6 - 30岁）这一大型且临床特征多样的样本，研究了皮质厚度的神经发育差异及其基因组基础。作者还研究了在感觉特征的严重程度和模式上存在差异的临床ASD亚组之间的神经发育差异及其潜在的病理生理机制。

结果

除了“核心”ASD脑区（即额颞叶和扣带回区域）存在显著的组间差异外，患有ASD的个体在更广泛的神经系统中，在神经典型皮质厚度范围内表现为神经解剖学异常值，该系统在遗传和/或转录组水平上富含已知与ASD相关的基因。在这些区域内，个体神经解剖学非典型性的总（即累积）程度与ASD和其他精神疾病的较高多基因评分显著相关，并且与症状严重程度的测量指标成比例。皮质厚度偏差的差异也与不同的感觉亚组相关，特别是在表达参与兴奋性而非抑制性神经传递相关基因的脑区。